drugs

1. COURSE TITLE: CLINICAL PHARMACY
COURSE CODE: 611 (T)
COURSE IN CHARGE: SHUMAILA QADIR (ON SHARING)
ANTI EPILEPTIC DRUGS

2. LEARNINGOBJECTIVES
CLASSIFICATION OF ANTIEPILEPTIC DRUGS
MODE OF ACTION
CHOICE OF DRUG IN DIFFERENT TYPES OF SEIZURES
DRUGS PROFILES OF CARBAMAZEPINES, PHENYTOIN, ETHOSUXIMIDE, BENZODIAZEPINES, PHENOBARBITALS
THERAPEUTIC USES
MODE OF ACTION
PHARMACOKINETICS
ADVERSE EFFECTS
DOSES

3. CLASSIFICATION OF ANTIEPILEPTICDRUGS
1.ACCORDING TO THE CHEMICAL CLASSIFICATION:
Hydantoins: phenytoin, phosphenytoin
Barbiturates: phenobarbitone
Iminostilbenes: carbamazepine, oxcarbazepine
Succinimides: ethosuximide
Aliphatic carboxylic acid: Valproic acid , divalproex
Benzodiazepines: clonazepam, diazepam, lorazepam
New compounds: gabapentin, lamotrigine, tiagabine, topiramate, vigabatrin, zonisamide, felbamate

4. CLASSIFICATION OFANTIEPILEPTICDRUGS
2. ACCORDING TO THE MODE OF ACTION:
i) Modulation of Ion Channels: Phenytoin, Carbamazepine, Lamotrigine, Oxcarbazine, Ethosuximide.
(ii) Potentiation of γ-amino Butyric Acid: Phenobarbital, Benzodiazepines, Vigabatrin, Tiagabine.
(iii) Drugs with multiple mechanism of action: Sodium Valproate, Gabapentin, Felbamate, Topiramate.
(iv) Drugs with unknown mechanism of action: Levetiracetam.

5. MODE OF ACTION
Modification of ion conductance
Prolongation of Na+ channel inactivation
Inhibition of `T` type Ca++ current
Increase inhibitory ( GABAergic ) transmission ,Cl - Channel.
Glutamate receptor antagonism (NMDA)

6. 1. (a)INHIBITIONOFUSE-DEPENDENTNA+CHANNEL
Many drugs ( e.g., phenytoin , carbamazepine , valproate , lamotrigine ) block the Na+ channels that remain
open due to repetitive neuronal firing, they block the use-dependent or voltage dependent Na+ channel
These drugs prolongs the duration of ‘inactivated phase’ delay its reversion to the resting phase, it reduces the
chances of becoming available for activation again
Sodium channels are responsible for the rising phase of the action potential in excitable cells and membranes
Examples: Phenytoin
Carbamazepine
Lamotrigine

7. 1. (b) TTYPECA++ CURRENTINHIBITION
Thalamic neurons exhibit prominent T current which is a low threshold Ca++ current
T type current is responsible for 3 Hz spike-and-wave
Ethosuximide is a major drug used for the treatment of absence seizures
It inhibits the low threshold Ca +2 currents which are responsible for generating the thalamic cortical rhythm
in the form of 3Hz spikes & waves seen in petit mal attack
Drugs : ethosuximide
valproate and
trimethadione

8. 2)ENHANCEMENTOFGABAERGICACTION
Some of the antiepileptic drugs ( e.g., Phenobarbital & benzodiazepines ) activates GABA A receptors , to facilitate GABA-mediated
opening of Cl channels
Benzodiazepines increases the frequency of opening of Cl channel
Phenobarbital increases the duration of opening of Cl channel
Vigabatrin inhibit the enzyme GABA transminase which is responsible to metabolise GABA thus increases the neuronal
concentration of GABA
Tigabine inhibits GABA uptake by inhibiting GABA uptake transporter in neurons & glia it enhances the availability & inhibitory
actions of GABA at postsynaptic GABA A receptors
Drugs that facilitate GABA or inhibit glutamate pathways more likely to induce amnesia& impairment of learning as side effect

9. GABAATRANSMISSION
BARBITURATES
primidone
BENZODIAZEPINES:
Clobazam
, clonazepam
diazapam
Tiagabine
 Vigabatrin

10. 3.BLOCKADEOFNMDARECEPTORS
Activation of NMDA receptors produces depolarizing responses & initiates seizure activity
Felbamate blocks NMDA receptors.
GLUTAMATE
 Major excitatory transmitter:
Mainly intracellular
Three receptor types:
 NMDA
Associated with sodium and calcium ions
Magnesium ions block
Other messengers act at NMDA site AMPA

12. ANTIEPILEPTICDRUGSFORDIFFERENTTYPESOFSEIZURES
SEIZURE TYPE
FIRST-LINE TREATMENT SECOND LINE TREATMENT
Partial seizures carbamazepine
Lamotrigine
Oxcarbazepine
Levetiracetam
Topiramate
Valproate
clobazam
Zonisamide
pregabalin
phenytoin
Gabapentin
Lacosamide

13. ANTIEPILEPTICDRUGSFORDIFFERENTTYPESOFSEIZURES
SEIZURE TYPE FIRST-LINE TREATMENT SECOND LINE TREATMENT
Generalised seizures
Tonic clonic
Tonic
clonic
Absence
Valproate sodium
Carbamazepine
Lamotrigine
Ethosuximide
Sodium valproate
Lamotrigine
Clobazam
Phenobarbital
Clonazepam
lamotrigine
Atypical absences
Atonic
Sodium valproate
clonazepam
Lamotrigine
Carbamazepine
Myoclonic Sodium valproate
clonazepam
Levetiracetam
Acetazolamide
Topiramate

14. DRUG PROFILE

15. CARBAMAZEPINE(IMINOSTILBENES)
USE/INDICATION:
Carbamazepine is structurally related to the tricyclic antidepressants. It is the drug of choice for simple and complex partial seizures
and for tonic–clonic seizures secondary to a focal discharge seizure, and it is effective in trigeminal neuralgia and in the prophylaxis
of mood swings in manic depressive illness
MECHANISM OF ACTION:
Mechanism of Action. Like phenytoin, carbamazepine limits the repetitive firing of action potentials evoked by a sustained
depolarization. This appears to be mediated by a slowing of the rate of recovery of voltage-activated Na+ channels from inactivation.
PHARMACOKINETICS
Carbamazepine is slowly but well absorbed following oral administration. Plasma t1/2 after a single dose is 25–60 hours, but on
chronic dosing this decreases to 10 hours, because of CYP450 enzyme induction. A controlled-release preparation reduces peak
plasma concentrations. It is indicated in patients with adverse effects (dizziness, diplopia and drowsiness) that occur only around
peak drug concentrations, and in patients who have difficulty in complying with three or more doses per day.

16. CARBAMAZEPINE(CONT)
ADVERSE EFFECTS:
Sedation, ataxia, giddiness, nystagmus, diplopia, blurred vision and slurred speech occur in 50% of patients with plasma levels over
8.5mg/L. Other effects include rash and (much more rarely) blood dyscrasia, cholestatic jaundice, renal impairment and
lymphadenopathy. Carbamazepine can cause hyponatraemia and water intoxication due to an antidiuretic action.
CONTRAINDICATION:
It is contraindicated in patients with atrioventricular (AV) conduction abnormalities and a history of bone marrow depression or
porphyria. Its use in pregnancy has been associated with fetal neural-tube defects and hypospadias.
DRUG INTERACTION:
Carbamazepine should not be combined with monoamine oxidase inhibitors. It is a potent enzyme inducer and, in particular, it
accelerates the metabolism of warfarin, theophylline and the oral contraceptive.

17. CARBAMAZEPINE(CONT)
DOSE:
A low starting dose is given twice daily followed by a slow increase in dose until seizures are controlled. Rapid metabolism or drug
failure if seizures continue. The therapeutic range is 4–12mg/L.
Antiepileptic drug Starting dose (mg) Average maintenance Doses/day (total mg/day)
carbamazepine 100 600–2400 2–4

18. PHENYTOIN (HYDANTOINS)
USES/INDICATION:
Phenytoin is effective in the treatment of tonic–clonic and partial seizures, including complex partial seizures.
MECHANISM OF ACTION:
Like carbamazepine, Phenytoin limits the repetitive firing of action potentials evoked by a sustained depolarization. This effect is
mediated by a slowing of the rate of recovery of voltage-activated Na+ channels from inactivation
PHARMACOKINETICS:
Phenytoin is extensively metabolized by the liver and less than 5% is excreted unchanged. At therapeutic concentrations, 90% of
phenytoin is bound to albumin and to two α-globulins which also bind thyroxine. In uraemia, displacement of phenytoin from plasma
protein binding results in lower total plasma concentration and a lower therapeutic range

19. PHENYTOIN (HYDANTOINS)CONT
ADVERSE EFFECTS:
Effects on nervous system, high concentrations produce a cerebellar syndrome (ataxia, nystagmus, intention tremor, dysarthria),
involuntary movements and sedation. Seizures may paradoxically increase with phenytoin intoxication. High concentrations cause
psychological disturbances, ‘allergic’ effects rashes, drug fever and hepatitis may occur. Oddly, but importantly, such patients can
show cross-sensitivity to carbamazepine. Gingival hyperplasia occurs in about 20% of all patients during chronic therapy and is
probably the most common manifestation of phenytoin toxicity in children and young adolescents.
DOSES:
Antiepileptic drug Starting dose (mg) Average maintenance Doses/day (total mg/day)
phenytoin 200–300 200–400 1–2

20. PHENOBARBITAL (BARBITURATES)
USES/INDICATION:
Phenobarbitals is an effective drug for tonic and partial seizures, but is sedative in adults and causes behavioral disturbances and
hyperkinesia in children. It has been used as a second-line drug for atypical absence, atonic and tonic seizures, but is obsolete.
Rebound seizures may occur on withdrawal.
MECHANISM OF ACTION:
The mechanism by which phenobarbital inhibits seizures likely involves potentiation of synaptic inhibition through an action on the
GABAA receptor. Phenobarbital increased the GABAA receptor–mediated current by increasing the duration of bursts of GABAA
receptor–mediated currents without changing the frequency of bursts
PHARMACOKINETICS:
It is 40% to 60% bound to plasma proteins and bound to a similar extent in tissues, including brain. Up to 25% of a dose is
eliminated by pH-dependent renal excretion of the unchanged drug; the remainder is inactivated by hepatic microsomal enzymes,
principally CYP2C9, with minor metabolism by CYP2C19 and CYP2E1.

21. PHENOBARBITAL (BARBITURATES)CONT
ADVERSE EFFECTS:
Sedation, the most frequent undesired effect of phenobarbital, is apparent to some extent in all patients upon initiation of therapy, but
tolerance develops during chronic medication. Nystagmus and ataxia occur at excessive dosage. Phenobarbital sometimes produces
irritability and hyperactivity in children, and agitation and confusion in the elderly.
DOSES:
Antiepileptic drug Starting dose (mg) Average maintenance Doses/day (total mg/day)
phenobarbital 60 60–180 1

22. ETHOSUXIMIDE(SUCCINIMIDES)
THERAPEUTIC USES:
Ethosuximide is effective against absence seizures but not tonic-clonic seizures.
MECHANISM OF ACTION:
Ethosuximide reduces low threshold Ca2+ currents (T currents) in thalamic neurons. The thalamus plays an important role in
generation of 3-Hz spike-and-wave rhythms typical of absence seizures. Neurons in the thalamus exhibit a large-amplitude T-current
spike that underlies bursts of action potentials and likely plays an important role in thalamic oscillatory activity such as 3Hz spike-
and-wave activity. Inhibition of T currents is the mechanism by which ethosuximide inhibits absence seizures.
PHARMACOKINETICS:
Approximately 25% of the drug is excreted unchanged in the urine. The remainder is metabolized by hepatic microsomal enzymes,
but whether CYPs are responsible is unknown.

23. ETHOSUXIMIDE(SUCCINIMIDES) CONT
ADVERSE EFFECTS:
The most common dose-related side effects are gastrointestinal complaints (nausea, vomiting, and anorexia) and CNS effects
(drowsiness, lethargy, euphoria, dizziness, headache, and hiccough). Some tolerance to these effects develops. Parkinson like
symptoms and photophobia also have been reported. Restlessness, agitation, anxiety, aggressiveness, inability to concentrate, and
other behavioral effects have occurred primarily in patients with a prior history of psychiatric disturbance.
DOSES: An initial daily dose of 250 mg in children (3 to 6 years old) and 500 mg in older children and adults is increased by 250-
mg increments at weekly intervals until seizures are adequately controlled or toxicity intervenes. Divided dosage is required
occasionally to prevent nausea or drowsiness associated with once-daily dosing. The usual maintenance dose is 20 mg/kg per day.
Increased caution is required if the daily dose exceeds 1500 mg in adults or 750 to 1000 mg in children.
Antiepileptic drug Starting dose (mg) Average maintenance Doses/day (total mg/day)
Ethosuximide 250 500–1500 1–2

24. BENZODIAZEPINES
THERAPEUTIC USES:
Clonazepam is useful in the therapy of absence seizures as well as myoclonic seizures in children. However, tolerance to its ant
seizure effects usually develops after 1 to 6 months of administration, after which some patients will no longer respond to
clonazepam at any dosage. While diazepam is an effective agent for treatment of status epilepticus, its short duration of action is a
disadvantage, leading to the more frequent use of lorazepam. Although diazepam is not useful as an oral agent for the treatment of
seizure disorders, clorazepate is effective in combination with certain other drugs in the treatment of partial seizures.
MECHANISM OF ACTION:
The antiseizure actions of the benzodiazepines, as well as other effects that occur at non sedating doses, result in large part from
their ability to enhance GABA-mediated synaptic inhibition. At therapeutically relevant concentrations, benzodiazepines act at subsets
of GABAA receptors and increase the frequency, but not duration, of openings at GABA-activated Cl– channels

25. BENZODIAZEPINES CONT
PHARMACOKINETICS:
Clonazepam is metabolized principally by reduction of the nitro group to produce inactive 7-amino derivatives. Less than 1% of the
drug is recovered unchanged in the urine. The half-life of clonazepam in plasma is about 1 day. Lorazepam is metabolized chiefly by
conjugation with glucuronic acid, its half-life in plasma is about 14 hours.
ADVERSE EFFECTS:
The principal side effects of long-term oral therapy with clonazepam are drowsiness and lethargy. These occur in about 50% of
patients initially, but tolerance often develops with continued administration. Cardiovascular and respiratory depression may occur after
the intravenous administration of diazepam, clonazepam, or lorazepam, particularly if other antiseizure agents or central depressants
have been administered previously.

26. BENZODIAZEPINES CONT
DOSES:
The initial dose of clonazepam for adults should not exceed 1.5 mg per day and for children 0.01 to 0.03 mg/kg per day. The dose-
dependent side effects are reduced if two or three divided doses are given each day. The dose may be increased every 3 days in
amounts of 0.25 to 0.5 mg per day in children and 0.5 to 1 mg per day in adults. The maximal recommended dose is 20 mg per day
for adults and 0.2 mg/kg per day for children. The maximal initial dose of clorazepate is 22.5 mg per day in three portions for adults
and 15 mg per day in two doses in children. Clorazepate is not recommended for children under the age of 9.
Antiepileptic drug Starting dose (mg) Average maintenance Doses/day (total mg/day)
clonazepam 0.5 0.5–3 1–2

27. SUMMARY
The pathophysiology of epilepsy and the mode of action of antiepileptic drugs are poorly understood. These agents are not all
sedative, but selectively block repetitive discharges at concentrations below those that block normal impulse conduction.
Carbamazepine and phenytoin prolong the inactivated state of the sodium channel and reduce the likelihood of repetitive action
potentials. Consequently, normal cerebral activity, which is associated with relatively low action potential frequencies, is unaffected,
whilst epileptic discharges are suppressed. γ-Aminobutyric acid (GABA) acts as an inhibitory neurotransmitter by opening chloride
channels that lead to hyperpolarization and suppression of epileptic discharges.
In addition to the receptor site for GABA, the GABAreceptor–channel complex includes benzodiazepine and barbiturate recognition
sites which can potentiate GABA anti-epileptic activity. Vigabatrin (γ-vinyl-γ-aminobutyric acid) irreversibly inhibits
GABAtransaminase, the enzyme that inactivates GABA. The resulting increase in synaptic GABAprobably explains its anti-epileptic
activity.
Glutamate is an excitatory neurotransmitter. A glutamate receptor, the N-methyl-D-aspartate (NMDA) receptor, is important in the
genesis and propagation of high-frequency discharges. Lamotrigine inhibits glutamate release and has anticonvulsant activity.

28. REFERENCES
A Textbook of Clinical Pharmacology and Therapeutics
FIFTH EDITION
JAMES M RITTER MA DPHIL FRCP FMedSci FBPHARMACOLS Professor of Clinical Pharmacology at King’s College London School of Medicine, Guy’s, King’s and
St Thomas’ Hospitals, London, UK
LIONEL D LEWIS MA MB BCH MD FRCP Professor of Medicine, Pharmacology and Toxicology at Dartmouth Medical School and the Dartmouth-Hitchcock Medical
Center, Lebanon, New Hampshire, USA
TIMOTHY GK MANT BSC FFPM FRCP Senior Medical Advisor, Quintiles, Guy's Drug Research Unit, and Visiting Professor at King’s College London School of
Medicine, Guy’s, King’s and St Thomas’ Hospitals, London, UK
ALBERT FERRO PHD FRCP FBPHARMACOLS Reader in Clinical Pharmacology and Honorary Consultant Physician at King’s College London School of Medicine,
Guy’s, King’s and St Thomas’ Hospitals, London, UK
Goodman& Gilman’s The Pharmacological Basis of THERAPEUTICS
eleventh edition
Clinical Pharmacy and Therapeutics
EditEd by Roger Walker bPharm, Phd, FRPharmS, FFPH